The present invention, in some embodiments thereof, relates to non-graft versus host disease (GVHD) inducing anti-third party cells comprising a central memory T-lymphocyte phenotype and, more particularly, but not exclusively, to the use of same for graft versus leukemia/lymphoma treatment.
Treatment options for patients with hematological malignancies such as non-Hodgkin lymphoma (NHL) are many and varied. These modern treatment protocols lead to complete remission (CR) in a considerable proportion of the patients. However, many of these patients ultimately relapse, implying that residual tumor cells remain in patients achieving a clinical CR. To address this challenge donor lymphocyte infusion (DLI) endowed with graft-versus-leukemia/lymphoma (GVL) reactivity are currently being developed. In particular, progress has been made in the context of allogeneic bone marrow transplantation (BMT) in conjunction with DLI after transplantation [Grigg A and Ritchie D, Biol Blood Marrow Transplant (2004) 10: 579-590]. Thus, it has been demonstrated that donor CD8+ T cells present in the stem cell graft or in DLI have the added benefit of GVL effect that can kill residual malignant cells [Ho W Y et al., J Clin Invest. (2002) 110: 1415-1417]. However, this benefit is offset by graft-versus-host disease (GVHD), associated with CD8 T cells, which adversely impact transplant-related mortality.
Previous work done by the present inventors has shown that ex-vivo stimulation of murine CD8+ T cells against 3rd-party stimulators, under IL-2 deprivation, leads to selective growth of 3rd-party restricted CD8+ cytotoxic T lymphocyte (CTL) clones which can facilitate T cell depleted BMT (TDBMT) engraftment without causing GVHD [Bachar-Lustig E. et al., Blood (2003) 102:1943-1950; Reich-Zeliger S. et al., Immunity (2000) 13: 507-515]. Recently, the present inventors demonstrated that activated anti-3rd party CD8+ cells with central memory phenotype (Tcm), can further support and improve bone marrow (BM) engraftment, likely due to the improved lymph node homing of the Tcm cells, their proliferative capacity and prolonged persistence in BMT recipients [Ophir E et al., Blood (2010) 115: 2095-2104].
Furthermore, the present inventors have shown that in humans, anti-3rd party CTLs, although depleted of alloreactivity, exhibit potent in-vitro killing of B-CLL and different types of primary lymphoma cells [Lask A et al. (submitted 2010); Arditti F D et al., Blood (2005) 105:3365-3371]. This unique form of GVL was shown to be independent of TCR recognition and it was found to be mediated both by autologous and by allogeneic anti-3rd party CTLs. Furthermore, this TCR independent killing of B cell malignancies by anti-3rd party CTLs was shown to be mediated via a rapid adhesion through ICAM1-LFA1 binding, followed by slow induction of apoptosis upon a critical interaction between CD8 on the CTL and MHC class I on the tumor cell. Moreover, the killing was shown to be independent of the classical CTLs death molecules: FASL, perforin, TNF, and Trail [Lask A et al., supra].
Additional background art includes WO/2010/049935.